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Abstract Background Despite the success of HMG-CoA reductase inhibitor (statin) therapy in reducing atherosclerotic cardiovascular events, a residual risk for cardiovascular events in patients with coronary artery disease (CAD) remains. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are promising anti-atherosclerosis agents that might reduce the residual CAD risk. Non-contrast T1-weighted imaging (T1WI) with cardiac magnetic resonance (CMR) less invasively identifies high-risk coronary plaques as high-intensity signals. These high-intensity plaques (HIPs) are quantitatively assessed using the plaque-to-myocardium signal intensity ratio (PMR). Our goal is to assess the effect of EPA/DHA on coronary HIPs detected with T1WI in patients with CAD on statin treatment. Methods/design This prospective, controlled, randomized, open-label study examines the effect of 12 months of EPA/DHA therapy and statin treatment on PMR of HIPs detected with CMR and computed tomography angiography (CTA) in patients with CAD. The primary endpoint is the change in PMR after EPA/DHA treatment. Secondary endpoints include changes in Hounsfield units, plaque volume, vessel area, and plaque area measured using CTA. Subjects are randomly assigned to either of three groups: the 2 g/day EPA/DHA group, the 4 g/day EPA/DHA group, or the no-treatment group. Discussion This trial will help assess whether EPA/DHA has an anti-atherosclerotic effect using PMR of HIPs detected by CMR. The trial outcomes will provide novel insights into the effect of EPA/DHA on high-risk coronary plaques and may provide new strategies for lowering the residual risk in patients with CAD on statin therapy. Trial registration The University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000015316 . Registered on 2 October 2014.

Background & Aims: Microbial molecular products incite intestinal inflammation by activating Toll-like receptors (TLRs) and inflammasomes of the innate immune system. This systemâs contribution to esophageal inflammation is not known. Gram-negative bacteria, which dominate the esophageal microbiome in reflux esophagitis, produce lipopolysaccharide (LPS), a TLR4 ligand. TLR4 signaling produces pro-interleukin (IL)1β, pro-IL18, and NOD-like receptor protein 3 (NLRP3), which prime the NLRP3 inflammasome. Subsequent NLRP3 inflammasome activation cleaves caspase-1, inducing secretion of proinflammatory cytokines and pyroptosis (inflammatory cell death). We explored LPS effects on NLRP3 inflammasome priming and activation in esophageal cells. Methods: We exposed esophageal squamous and Barrettâs epithelial cells to LPS and measured the following: (1) TLR4, pro-IL1β, pro-IL18, and NLRP3 expression; (2) caspase-1 activity; (3) tumor necrosis factor-α, IL8, IL1β, and IL18 secretion; (4) lactate dehydrogenase (LDH) release (a pyroptosis marker); and (5) mitochondrial reactive oxygen species (ROS). As inhibitors, we used acetyl-Tyr-Val-Ala-Asp-CHO for caspase-1, small interfering RNA for NLRP3, and (2-(2,2,6,6,-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride for mitochondrial ROS. Results: Squamous and Barrettâs cells expressed similar levels of TLR4, but LPS induced TLR4 signaling that increased tumor necrosis factor-α and IL8 secretion only in Barrettâs cells. Barrettâs cells treated with LPS showed increased expression of pro-IL18, pro-IL1β, and NLRP3, and increased mitochondrial ROS levels, caspase-1 activity, IL1β and IL18 secretion, and LDH release. Acetyl-Tyr-Val-Ala-Asp-CHO, NLRP3 small interfering RNA, and Mito-TEMPO all blocked LPS-induced IL1β and IL18 secretion and LDH release. Conclusions: In Barrettâs cells, LPS both primes and activates the NLRP3 inflammasome, causing secretion of proinflammatory cytokines and pyroptosis. By triggering molecular events promoting inflammation, the esophageal microbiome might contribute to inflammation-mediated carcinogenesis in Barrettâs esophagus. Keywords: IL1β, Pyroptosis, Esophageal Squamous Cell, GERD, Cytokine

Background and study aim: The incidence of stricture formation caused by endoscopic submucosal dissection (ESD) for widespread lesions is high, and stricture formation can reduce quality of life. We evaluated the prophylactic efficacy of hybrid therapy using a locoregional steroid injection and polyglycolic acid (PGA) sheets with fibrin glue to prevent stricture formation after esophageal ESD in high risk patients in whom we predicted stricture formation would be difficult to prevent with a single prophylactic steroid injection. Methods: Ten patients who underwent esophageal ESD were enrolled (entire-circumference: n = 6; sub-circumference, more than 5/6 of the circumference: n = 4). A single locoregional steroid injection and PGA sheets with fibrin glue were used after ESD. We evaluated the incidence of stricture formation, the number of endoscopic balloon dilation (EBD) procedures needed to treat the stricture formation, and adverse events of the therapy. Results: Esophageal stricture formation occurred in 50.0 % of patients (5/10) (median EBD sessions 0.5, range 0 – 16). Subanalysis showed that stricture formation occurred in 37.5 % of patients (3/8) excluded the lesions located near a previous scar from ESD or surgical anastomosis site (median EBD sessions 0, range 0 – 4). Conclusion: Hybrid therapy using a locoregional steroid injection and PGA sheets with fibrin glue may have the potential to prevent esophageal stricture formation after esophageal ESD in high risk patients.

Smoking is associated with gastroesophageal reflux disease (GERD). Varenicline, a nicotinic receptor partial agonist, is used to aid smoking cessation. The purpose of this study was to prospectively examine the long-term benefits of smoking cessation on GERD and health-related quality of life (HR-QOL).Patients treated with varenicline were asked to fill out a self-report questionnaire about their smoking habits, gastrointestinal symptoms, and HR-QOL before and 1 year after smoking cessation. The prevalence of GERD, frequency of symptoms, and HR-QOL scores were compared. We also investigated associations between clinical factors and newly-developed GERD.A total of 141 patients achieved smoking cessation (success group) and 50 did not (failure group) at 1 year after the treatment. The GERD improvement in the success group (43.9%) was significantly higher than that in the failure group (18.2%). The frequency of reflux symptoms significantly decreased only in the success group. There were no significant associations between newly developed GERD and clinical factors including increased body mass index and successful smoking cessation. HR-QOL significantly improved only in the success group.Smoking cessation improved both GERD and HR-QOL. Smoking cessation should be recommended for GERD patients.

In patients with cardiac sarcoidosis, ventricular tachycardia (VT) is observed in some cases. However, effective therapies for the VT are still unknown. Case: A 50-year old female with cardiac sarcoidosis underwent DDD pacemaker implantation for a high degree atrioventricular block with symptoms of faintness and shortness of breath. One month after the surgery, she was admitted for frequent episodes of non-sustained VT. In the electrophysiologic study (EPS), sustained monomorphic VT and ventricular fibrillation were induced; therefore pacemaker was replaced with implantable cardioverter-defibrillator (ICD). Amiodarone was started orally but it couldn't suppress frequent VT episodes, and frequent ICD shocks were delivered. When the oral steroid therapy was initiated for the cardiac sarcoidosis, it not only suppressed the frequent VT but also improved the atrioventricular nodal dysfunction. In conclusion, steroid therapy might be an option to consider in cardiac sarcoidosis with refractory VT.

Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant.We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy.We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks.The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated.High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.UMIN Clinical Trials Registry UMIN000003463.

Background and Study Aims There are a few reports about the efficacy of endoscopic submucosal dissection (ESD) for adenocarcinomas of the esophagogastric junction (EGJ). However, there is no detailed analysis that divides EGJ cancers into Barrett’s adenocarcinoma and gastric cardia adenocarcinoma. The aim of this study was to analyze the efficacy of ESD for EGJ cancers, comparing these two adenocarcinomas. Patients and Methods This study included 43 patients who underwent ESD for type II EGJ cancers between 2004 and 2011. Pathological examination of resected specimens confirmed 14 cases of Barrett’s adenocarcinoma and 29 cases of gastric cardia adenocarcinoma. Cutting margins on the oral side were placed 1 cm from the squamocolumnar junction, or 1 cm away from the slight elevation that is an endoscopic sign of subsquamous carcinoma extension. Clinical outcomes, prevalence and length of subsquamous carcinoma extension, and long-term outcomes were compared between these two types of adenocarcinoma. Results No significant differences in clinical outcomes were found between these two types of adenocarcinoma (en bloc, 100 % versus 100 %; complete, 100 % versus 89.7 %; curative, 85.7 % versus 75.9 %). No serious adverse events were encountered. The prevalence of subsquamous carcinoma extension was significantly higher in Barrett’s adenocarcinoma compared with gastric cardia adenocarcinoma. Local and distant recurrence were not observed in any cases with curative resection during the follow-up period (1.6 – 87.6 months). Conclusion ESD for EGJ cancers, including both Barrett’s adenocarcinoma and gastric cardia adenocarcinoma, was efficient and useful. ESD with a 1 cm safety margin may be acceptable for EGJ cancers.

Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-α and ICAM-1.

BACKGROUND & AIMS: Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Proton pump inhibitor (PPI) therapy improves subjective but not objective sleep parameters in patients with GERD. This study aimed to investigate the association between GERD and sleep, and the effect of PPI on sleep by using a rat model of chronic acid reflux esophagitis. METHODS: Acid reflux esophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and then wrapping the duodenum near the pylorus. Rats underwent surgery for implantation of electrodes for electroencephalogram and electromyogram recordings, and they were transferred to a soundproof recording chamber. Polygraphic recordings were scored by using 10-s epochs for wake, rapid eye movement sleep, and non-rapid eye movement (NREM) sleep. To examine the role of acid reflux, rats were subcutaneously administered a PPI, omeprazole, at a dose of 20 mg/kg once daily. RESULTS: Rats with reflux esophagitis presented with several erosions, ulcers, and mucosal thickening with basal hyperplasia and marked inflammatory infiltration. The reflux esophagitis group showed a 34.0% increase in wake (232.2±11.4 min and 173.3±7.4 min in the reflux esophagitis and control groups, respectively; p

High-mobility group box 1 (HMGB1) was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor (TLR) 2, TLR4, and receptor for advanced glycation end products (RAGE), leading to tissue injury. Although HMGB1's ability to induce inflammation has been well documented, no studies have examined the role of HMGB1 in wound healing in the gastrointestinal field. The aim of this study was to evaluate the role of HMGB1 and its receptors in the healing of gastric ulcers. We also investigated which receptor among TLR2, TLR4, or RAGE mediates HMGB1's effects on ulcer healing. Gastric ulcers were induced by serosal application of acetic acid in mice, and gastric tissues were processed for further evaluation. The induction of ulcer increased the immunohistochemical staining of cytoplasmic HMGB1 and elevated serum HMGB1 levels. Ulcer size, myeloperoxidase (MPO) activity, and the expression of tumor necrosis factor α (TNFα) mRNA peaked on day 4. Intraperitoneal administration of HMGB1 delayed ulcer healing and elevated MPO activity and TNFα expression. In contrast, administration of anti-HMGB1 antibody promoted ulcer healing and reduced MPO activity and TNFα expression. TLR4 and RAGE deficiency enhanced ulcer healing and reduced the level of TNFα, whereas ulcer healing in TLR2 knockout (KO) mice was similar to that in wild-type mice. In TLR4 KO and RAGE KO mice, exogenous HMGB1 did not affect ulcer healing and TNFα expression. Thus, we showed that HMGB1 is a complicating factor in the gastric ulcer healing process, which acts through TLR4 and RAGE to induce excessive inflammatory responses.

Iron is an essential metal for living organisms but its level must be strictly controlled in cells, because ferrous ion induces toxicity by generating highly active reactive oxygen, hydroxyl radicals, through the Fenton reaction. In addition, ferric ion shows low solubility under physiological conditions. To overcome these obstacles living organisms possess Ferritin superfamily proteins that are distributed in all three domains of life: bacteria, archaea, and eukaryotes. These proteins minimize hydroxyl radical formation by ferroxidase activity that converts Fe(2+) into Fe(3+) and sequesters iron by storing it as a mineral inside a protein cage. In this study, we discovered that mycobacterial DNA-binding protein 1 (MDP1), a histone-like protein, has similar activity to ferritin superfamily proteins. MDP1 prevented the Fenton reaction and protects DNA by the ferroxidase activity. The K(m) values of the ferroxidase activity by MDP1 of Mycobacterium bovis bacillus Calmette-Guérin (BCG-3007c), Mycobacterium tuberculosis (Rv2986c), and Mycobacterium leprae (ML1683; ML-LBP) were 0.292, 0.252, and 0.129 mM, respectively. Furthermore, one MDP1 molecule directly captured 81.4±19.1 iron atoms, suggesting the role of this protein in iron storage. This study describes for the first time a ferroxidase-iron storage protein outside of the ferritin superfamily proteins and the protective role of this bacterial protein from DNA damage.

Objective: To determine safety and efficacy of cardiac rehabilitation (CR) initiated immediately following balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) who presented with continuing exercise intolerance and symptoms on effort even after a course of BPA; 2-8 sessions/patient.Methods: Forty-one consecutive patients with inoperable CTEPH who underwent their final BPA with improved resting mean pulmonary arterial pressure of 24.7±5.5 mm Hg and who suffered remaining exercise intolerance were prospectively studied. Participants were divided into two groups just after the final BPA (6.8±2.3 days): patients with (CR group, n=17) or without (non-CR group, n=24) participation in a 12-week CR of 1-week inhospital training followed by an 11-week outpatient programme. Cardiopulmonary exercise testing, haemodynamics, and quality of life (QOL) were assessed before and after CR.Results: No significant between-group differences were found for any baseline characteristics. At week 12, peak oxygen uptake (VO2), per cent predicted peak VO2 (70.7±9.4% to 78.2±12.8%, p<0.01), peak workload, and oxygen pulse significantly improved in the CR group compared with the non-CR group, with a tendency towards improvement in mental health-related QOL. Quadriceps strength and heart failure (HF) symptoms (WHO functional class, 2.2-1.8, p=0.01) significantly improved within the CR group. During the CR, no patient experienced adverse events or deterioration of right-sided HF or haemodynamics as confirmed via catheterisation.Conclusions: The combination of BPA and subsequent CR is a new treatment strategy for inoperable CTEPH to improve exercise capacity to near-normal levels and HF symptoms, with a good safety profile. [ABSTRACT FROM AUTHOR]

Background and Aim: Mucosal healing is now the ideal treatment goal for patients with Crohn’s disease (CD) and endoscopy is suitable for both visualizing the intestinal mucosa and optimizing treatment according to the objective endoscopic findings; however, passing through strictures with a conventional colonoscope is sometimes difficult. An ultrathin colonoscope (outer diameter 9.2 mm) has been developed for superior insertion performance. Methods: CD patients with strictures that could not be passed with a conventional colonoscope were eligible for entry into the study. We investigated the rate of passage of the ultrathin colonoscope beyond strictures. We also investigated the clinical impact of optimizing the treatment strategy according to the endoscopic findings beyond the stricture. Results: Of 49 patients, the ultrathin colonoscope could pass the stricture in 59.2% (29/49). The main reason for failure compared with the “pass” group was anal stricture (P = 0.005). When including finger bougie for severe anal stricture, passage of the stricture was achieved in 83.7% (41/49) of cases and the oral mucosa beyond the stricture was visualized. In these cases, 56.1% (23/41) had treatment efficacy confirmed and 43.9% (18/41) required a change of treatment. Importantly, half (9/18) of them were in clinical remission. There were no complications of the study. Conclusion: The ultrathin colonoscope could provide optimized treatment based on objective findings of the activity of the oral-side mucosa in CD patients complicated with stricture. Selection of the appropriate endoscope to visualize the responsible lesion is essential to optimize the treatment strategy in each case of CD. [ABSTRACT FROM AUTHOR]

Background and Aim: Approximately more than half of patients with non-erosive reflux disease (NERD) do not respond to proton pump inhibitor (PPI) therapy. Although NERD is a heterogeneous entity, previous study showed that multichannel intraluminal impedance (MII)-pH monitoring could distinguish reflux-related disease from PPI-refractory NERD. The aim of this study was to examine the usefulness of baseline impedance in PPIrefractory NERD patients. Methods: We used MII-pH monitoring to analyze reflux parameters, symptom index (SI), and baseline impedance in 37 PPI-refractory NERD patients on PPI. Reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified as having reflux-related disease based on abnormal reflux parameters or positive SI (≥ 50%), or non-reflux-related disease, including functional heartburn, based on negative SI with normal reflux parameters. Results: A total of 26 of the 37 subjects were diagnosed with reflux-related disease, including eight with acid-reflux type and 18 with non-acid-reflux type, and nine with functional heartburn and two with pseudohypersalivation. There were no significant differences in the clinical characteristics of the acid-reflux type, non-acid-reflux type, and functional heartburn groups. The baseline impedance value in the acid-reflux type (1245 ± 392 Ω) was significantly lower than that in the non-acid-reflux type (2824 ± 1160 Ω) and functional heartburn (3546 ± 1353 Ω) groups. Baseline impedance values inversely correlated with reflux percent time, acid-reflux time, and acid exposure time. Conclusion: Among patients with PPI-refractory NERD, acid-reflux type was associated with lower baseline impedance compared with non-acid-reflux type and functional heartburn. [ABSTRACT FROM AUTHOR]

Gastroenterological reflux disease and functional dyspepsia are usually treatable using Western medical practices. Nonetheless, some cases present with intractable symptoms that are not amenable to these therapies. Treatment with kampo, a traditional Japanese medicine, recently has been proposed as an alternative therapy for use in combination with the Western practices. In general, traditional Japanese medicines have been used empirically for intractable symptoms correctively designated as "general malaises." Accumulating lines of evidence, including basic and clinical researches, have demonstrate detailed mechanisms where traditional Japanese medicines exert pharmacological action to improve symptoms. Therefore, traditional Japanese medicines have been gaining use by various medical doctors as the specific modes of pharmacological action are recognized. This review covers both the pharmacological functions and the clinical efficacies of rikkunshito for use in treating disorders of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Patients with dyspepsia/functional dyspepsia (FD) show frequent overlapping of other gastrointestinal (GI) diseases, such as irritable bowel syndrome, and non-GI diseases, in addition to internal subgroup overlapping. These overlap patients have more frequent or more severe symptoms, poorer health-related quality of life and higher somatization scores, and they are more likely to experience anxiety, depression or insomnia compared to non-overlap patients. The higher prevalence of overlap in patients with dyspepsia/FD is not by chance, indicating common pathogeneses, including visceral hypersensitivity, altered GI motility, infection, and stressful early life events. There are few clinical trials targeting overlap in patients with dyspepsia/FD, and no therapeutic strategy has been established. Further studies in this research area are needed. In this review, we describe the epidemiology, pathogenesis and treatment of overlap in patients with dyspepsia/FD. [ABSTRACT FROM AUTHOR]

Background There are few comprehensive reports detailing the prevalence of major adverse events associated with a double-balloon enteroscopy procedure. Methods We retrospectively investigated the prevalence of major adverse events in 538 patients (262 males and 276 females; median age, 65 years; age range, 12-95 years) who underwent double-balloon enteroscopy at our Institution between April 2008 and October 2011. Results Of the 17 adverse events recorded (3.2%), acute pancreatitis (n = 5; 0.9%) occurred during both diagnostic (n = 3) and therapeutic (n = 2) anterograde double-balloon enteroscopy, and all of them were treated conservatively. For these cases, the average duration of the examination was 135 min, which was longer than for the other patients (97 min) (P = 0.046). Intestinal bleeding (1.3%) was observed in 6 cases after endoscopic polypectomy and in 1 case following a biopsy procedure during a diagnostic double-balloon enteroscopy. The prevalence rates of intestinal perforation and other complications were 0.2% and 0.7%, respectively. Conclusions The rate of adverse events associated with double-balloon enteroscopy was high compared to that associated with conventional upper/lower gastrointestinal endoscopy (0.042%/0.078%). The occurrence of acute pancreatitis may be significantly dependent on the duration of double-balloon enteroscopy examination. [ABSTRACT FROM AUTHOR]

Objective The role of tumour necrosis factor α (TNFα) in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains unclear. We evaluated the preventive effect of anti-TNF therapy against NSAID-induced enteropathy in rheumatoid arthritis (RA) patients. Design Capsule endoscopy was performed in 95 consecutive RA patients who received NSAID for more than 3 months, with or without anti-TNF therapy over a period of 3 months. The findings were scored from 0 to 4: 0, normal; 1, red spots; 2, one to four erosions; 3, more than four erosions; and 4, large erosions/ulcers. The relationship between the use of anti-TNF therapy and the risk of severe damage (scores 3 or 4) or the most severe damage (score 4) was assessed using multiple logistic regression analysis. Furthermore, a propensity score matching analysis was performed to reduce the effects of TNF selection bias. Results By stratifying the patients on the basis of anti- TNF therapy, we obtained crude OR of 0.23 for severe damage (95% CI 0.09 to 0.65) and 0.37 for the most severe damage (95% CI 0.16 to 0.86). This protective effect of anti-TNF therapy remained robust to adjustments for baseline characteristics, with the adjusted OR for severe damage and the most severe damage ranging from 0.23 to 0.26 and 0.06 to 0.41, respectively. Propensity score matching yielded similar results and showed the protective effects of anti-TNF therapy against severe and most severe damage. Conclusions Anti-TNF therapy may protect against NSAID-induced small intestinal damage in RA patients. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase- 2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE2 concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE2 reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression. [ABSTRACT FROM AUTHOR]

Background and Aim. New diagnostic or therapeutic methods in endoscopy have been used. Current clinical application of these procedures is not well known. The aim of this study is to investigate the present situation on endoscopic diagnosis and treatment of gastrointestinal disorders in East Asian countries. Method. A representative member from the International Gastrointestinal Consensus Symposium Committee provided a questionnaire to physicians in China, Indonesia, Japan, Korea, the Philippines, and Thailand. Results. In total, 514 physicians including gastroenterologists, surgeons, and general practitioners enrolled. The most frequently occurring disorder as the origin of upper gastrointestinal bleeding is gastric ulcer. Capsule endoscopy is selected as the first choice for the diagnosis of small intestine bleeding. The second choice was double-balloon endoscopy or angiography. For patients with gastric adenoma, the number of physicians who choose endoscopic mucosal resection is larger than those selecting endoscopic submucosal dissection (ESD) in China, Indonesia, the Philippines, and Thailand. ESD is chosen first in Japan and Korea. Conclusion. New instruments or techniques on endoscopy have not come into wide use yet, and there is diversity in the situation on it in Asian countries.We should unify the endoscopic diagnostic criteria or treated strategy in patients with GI disease. [ABSTRACT FROM AUTHOR]

Background/Aims: Gastroesophageal reflux disease (GERD) is a common gastrointestinal disease. This study was designed to examine current epidemiology, diagnosis, management, and treatment of patients diagnosed with GERD by surveying physicians in several East Asian countries. Methods: A questionnaire-based survey was completed in six countries including China, Indonesia, Japan, Korea, the Philippines, and Thailand between July 2008 and December 2008. Results: In total, 876 physicians participated in the study. Most physicians in all countries, except Japan, frequently used international guidelines for the care of GERD patients, whereas approximately half of Japanese physicians did not use such guidelines. GERD was common among many patients, but Barrett’s esophagus, particularly the long-segmental type, was rare. The incidence of esophageal cancer, particularly adenocarcinoma, was high in China, but low in other countries. Most physicians diagnosed GERD based on symptoms, followed by endoscopy in Japan and Korea, or in other countries, by the proton-pump inhibitor (PPI) test. Heartburn was recognized as the chief complaint in all countries except Korea. Most physicians in all countries used PPI as the first-line of treatment for GERD. Increasing the PPI dose was the treatment of choice for PPI-refractory erosive esophagitis in Korea, the Philippines, and Thailand. In contrast, in other countries, physicians used a combination of PPI and other drugs to treat PPI-refractory erosive esophagitis. Prescription of antidepressant drugs increased for PPI-refractory nonerosive reflux disease compared with PPI-refractory erosive esophagitis. Conclusion: The findings in the present survey are useful to understand the current epidemiology, diagnosis, and treatment of GERD in East Asian countries. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract  Pravastatin, an HMG-CoA reductase inhibitor, exerts anti-inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase (eNOS). We investigated the effect of pravastatin on Helicobacter pylori-induced gastritis in mice. Mice with or without H. pylori infection received intraperitoneal pravastatin daily for 1 week. Expression of eNOS mRNA and tumor necrosis factor-α mRNA and myeloperoxidase activity in gastric tissue was determined. Myeloperoxidase activity was reduced in a dose-dependent manner by pravastatin, with activity inhibited by 53.5 and 73.7% at doses of 0.3 and 1 mg/kg, respectively. At a dose of 1 mg/kg, pravastatin reduced the level of tumor necrosis factor-α mRNA by 52.7%, while it did not affect eNOS expression. Pravastatin had no effects on these inflammatory parameters in uninfected mice. Pravastatin did not affect the viability of H. pylori. In conclusion, pravastatin exerts an anti-inflammatory effect on H. pylori-induced gastritis in mice without affecting eNOS expression. [ABSTRACT FROM AUTHOR]

Abnormalities in humoral immunity are implicated in the pathogenesis of ulcerative colitis. However, the detailed mechanisms of B-cell activation in the locale remain unaccounted for. We analyzed ulcerative colitis from the standpoint of lymphocytic expansion in the loco. Intestinal specimens obtained at surgery from 30 patients with ulcerative colitis treated with corticosteroids and 15 with Crohn’s disease were analyzed by immunohistochemistry and flow cytometry. Ulcerative colitis was characterized by a diffuse distribution of Ki-67+ small round cells particularly in the ulcer base (that were CD19+ and CD20–), with a significant number of them also CD138+. Immunoelectron microscopy for CD19 revealed an abundance of rough endoplasmic reticulum in the cytoplasm. These indicated that they are of immature plasma lineage cells. By contrast, plasma cells in Crohn’s disease were negative for CD19, and the labeling for Ki-67 was infrequent, showing mature phenotype. Flow cytometry revealed an occurrence of CD19+ and CD20– cells in ulcerative colitis but not in Crohn’s disease. The labeling index of Ki-67 among CD19+ plasma cells was positively correlated with the clinical activity of ulcerative colitis. High labeling of Ki-67 in CD19+ plasma cells is specific for active ulcerative colitis that was resistant to medical treatment by corticosteroids. [ABSTRACT FROM AUTHOR]

The article reports on 47-year-old Japanese man with Von Hippel-Lindau (VHL) disease who was admitted to the hospital for further examination of anemia, although he had no evidence of gastrointestinal bleeding such as hematemesis. He had undergone surgery for cerebellar hemangioblastoma at the age of 28 years and thereafter had undergone neurosurgery four times. At the age of 32, a huge serous cystadenoma of the pancreas and bilateral renal cysts were detected by CT scan. VHL disease is an autosomal dominant hereditary disorder characterized by a predisposition to develop a variety of neoplasms in multiple target organs.

A 31-year-old man with Crohn’s disease developed arthritis, spiking fever, and skin rash indistinguishable from that of adult­onset Still’s disease. He was admitted to our hospital because of a periumbilical intestinal skin fistula. Crohn’s disease had been diagnosed in 1991, and had required intestinal resection twice, and schizophrenia had been diagnosed in 1993. He developed polyarthritis and spiking fever, accompanied by a macular skin rash on both forearms. Marked hepatosplenomegaly and bilateral pleural effusion were detected on computed tomography examination. These findings are indistinguishable from those of adult-onset Still’s disease. Because his mental status had deteriorated following high-dose prednisolone on a previous admission, he was treated with an immunosuppressive agent on this occasion, with the treatment being successful. This is the first report of adult-onset Still’s disease complicating Crohn’s disease. In patients with Crohn’s disease, polyarthritis and skin rash can easily be misdiagnosed as enteropathic arthritis with erythema nodosum associated with the Crohn’s disease. Although adult-onset Still’s disease may not be fatal, early diagnosis is important because it can, in rare cases, result in lifethreatening complications. [ABSTRACT FROM AUTHOR]

Abstract. Granulomatous colitis is a major entity of human intestinal diseases. We previously reported that intravenous injection of mycobacterial cord factor (CF), a potent macrophage activator, induced pulmonary granulomas in mice with enhanced production of Th1 cytokines and chemokines. In this study we made a murine model of granulomatous colitis by intramural injection of CF. A single dose of 300 µg CF was injected into the wall of the rat and mouse colon in the form of liposomes. After 1 week granulomas developed at the injection site, extending from the subserosa to the lamina propria, and persisted for longer than 6 weeks. They were composed mainly of ED1-positive macrophages, which often underwent apoptosis, and CD4+ and CD8+ lymphocytes, which preferentially infiltrated around the macrophage accumulation. Myofibroblast proliferation was not prominent, and no appreciable fibrosis resulted after the decline of granulomas. Although the intestinal epithelium was involved in inflammation, tissue injuries such as mucosal erosion or ulceration were not induced. When granulomas were formed near the Peyer's patches, they invaded deeply into the lymphoid tissue, producing many small islands. The mesenteric lymph nodes also had many granulomatous islands in the cortex and medulla, but the liver and spleen displayed no granulomatous changes, suggesting that liposomal CF spreads via the lymphatic vessels from the injection site. The CF-induced colonic granulomas associated with mesenteric lymphadenitis will be useful for investigating human granulomatous colitis. [ABSTRACT FROM AUTHOR]